Impact of plasma-protein binding on receptor occupancy: an analytical description.
In this paper we analyse the dynamics of an inhibitor I which can either bind to a receptor R or to a plasma protein P. Assuming typical association and dissociation rates, we find that after an initial dose of inhibitor, there are three time scales: a short one, measured in fractions of seconds, in which the inhibitor concentration and the plasma-protein complex jump to quasi-stationary values, a medium one, measured in seconds in which the receptor complex rises to an equilibrium value and a large one, measured in hours in which the inhibitor-receptor complex slowly drops down to zero. We show that the average receptor occupancy, the pharmacologically relevant quantity, taken over, say, 24h reaches a maximal value for a specific value of the plasma-protein binding constant. Potentially, understanding and exploiting this optimum could be of great interest to those involved in drug discovery and development.
Peletier
Lambertus A
LA
Mathematical Institute, Leiden University, Leiden, The Netherlands. peletier@math.leidenuniv.nl
Benson
Neil
N
van der Graaf
Piet H
PH
D001798:Blood Proteins / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000097:blood; D010949:Plasma / Q000378:metabolism*; D011485:Protein Binding; D011955:Receptors, Drug / Q000097:blood; D012709:Serum Albumin / Q000378:metabolism
D001798:Blood Proteins; D004364:Pharmaceutical Preparations; D011955:Receptors, Drug; D012709:Serum Albumin